Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptors (NR) superfamily, as well as a transcription factor regulated by hormones. Different from other hormone-activated receptors, PPAR is located in the cytoplasm and then transferred into nucleus after being bound by an activated ligand; and subsequently, the complex binds to DNA response elements to activate their downstream gene expression (Glass et al., Genes Dev (2000) 14, 121-141). PPAR is a typical receptor, activated by metabolites, and is located in the nucleus. There are three types of PPARs that have been identified as α, β/δ and γ, each of which binds to a retinoid-X-receptor (RXR) to form a heterodimer receptor. The main function of PPAR β/δ is to regulate the proliferation and differentiation of gut cells. PPARγ is expressed in adipocytes, skeletal muscle cells, osteoclasts, osteoblasts and some immune cells, and its function is similar to PPARα. It was reported that it is lethal, to the subject, to knock out the PPARγ gene. The human species only has four genotypes of PPARγ, but only expresses PPARG-1 and PPARG-2 proteins in normal cells. PPARG-1 proteins are expressed extensively in cells, while PPARG-2 proteins are mainly limited to adipocytes.
It was also reported that PPARγ, activated by ligands, increased ligand-unrelated transcription activity through phosphorylation (Diradourian et al., Biochimie (2005) 87, 33-38). It was demonstrated that not only did PPARγ function as a transcription factor, PPARγ also inhibited inflammation-related gene expression by sumoylation through ligand activation. It is concluded that the function of inflammation related genes expression inhibition depends on binding the sumoylated PPARγ protein and the DNA repressor complex with the inflammation related genes, thereby preventing the 19S proteasome from degrading the repressor (Pascual et al., Nature (2005)437, 759-763).
It was reported in animal and human trials that a PPARγ activator was effective in treating diabetes and also provided anti-inflammation uses. PPARγ agonist Rosiglitazone, a type of glucocorticoid, was found to be effective in treating asthma in murine model or human trial (Narala et al., Respir Res (2007) 8, 90). Dominant negative mutation of human PPARγ results in a stereotyped syndrome of partial lipodystrophy and insulin resistance (Semple et al., J. Clin. Invest. (2006) 116, 581-589). PPARγ agonist was also often used for treating type II diabetes, e.g. pioglitazone and Rosiglitazone. It was also found that PPARγ agonist was effective in reducing bone loss and inflammation in the rheumatoid arthritis rat model (Koufany et al., Arthritis Res Ther (2008) 10, R6; Doshi et al., Expert Opin. Investig. Drugs (2010) 19(4), 489-512). In clinical trials, Rosiglitazone was also found to be effective in treating lipodystrophy (Anghel et al., Cell Res (2007) 17, 486-511).
Therefore, a new approach for enhancing PPARγ expression is desirable.